PROJECT SUMMARY Opiate abuse is a rapidly growing public health problem in the U.S. for which new treatments are desperately needed. There is evidence that the neuropeptide galanin may be an effective therapeutic target for opiate abuse. Galanin is strongly expressed in both animals and humans in the noradrenergic locus coeruleus (LC), an arousal and stress-responsive nucleus of the brain that is implicated in drug addiction. Preclinical studies indicate that galanin attenuates the rewarding effects of opiates, withdrawal symptoms, and relapse-like behavior. However, before galaninergic therapies can be considered for humans, the neuroanatomical source of galanin?s anti- addiction effects must be identified, and galanin?s ability to modulate opiate use must be evaluated. These questions have not yet been addressed because tools for manipulating galanin in a cell type-specific manner exist exclusively in mouse, and few labs are proficient at operant intravenous self-administration (SA) - the gold standard for studying animal drug use - in this species. Given our lab?s access to genetically modified mice with altered levels of LC galanin, viral vectors that target optogenetic proteins to LC noradrenergic neurons, and experience in self-administration, we are uniquely equipped to test the hypothesis that LC-derived galanin opposes opiate addiction-like behaviors and that central galanin attenuates opiate use. Aim 1 will determine whether LC-derived galanin protects against behavioral measures of opiate addiction by comparing morphine reward and withdrawal symptoms between wild-type mice and genetically modified mice that lack galanin specifically in LC neurons at baseline and with optogenetic stimulation of LC neurons. Aim 2 will determine whether galanin?s protective effects against opiate reward extend to opiate use by comparing morphine SA profiles in mice with either normal or genetically depleted central galanin. This study will be the first to 1) determine whether the LC is the neuroanatomical source of galanin that protects against opiate abuse and 2) directly test the effect of galanin on opiate use. In the long term, this research could lay the foundation for pre- clinical evidence supporting the use of LC/galaninergic therapies in humans with opiate addiction.